Kidney Week

Abstract: TH-PO170

Canagliflozin Treatment Impact on Collagen Type III Turnover Is Associated with a Reduced Mortality Risk in CANVAS

Session Information

• Diabetic Kidney Disease: Clinical - I
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 702 Diabetic Kidney Disease: Clinical

Authors

• Genovese, Federica, Nordic Bioscience, Herlev, Herlev , Denmark

Federica Genovese,

• Rasmussen, Daniel Guldager Kring, Nordic Bioscience, Herlev, Herlev , Denmark

Daniel Guldager Kring Rasmussen,

• Neal, Bruce, The George Institute for Global Health, Sydney, New South Wales, Australia

Bruce Neal,

• Karsdal, Morten Asser, Nordic Bioscience, Herlev, Herlev , Denmark

Morten Asser Karsdal,

• Hansen, Michael K., Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Michael K. Hansen,

Background

The precise mechanism underlying the beneficial effects of SGLT2 inhibition remains uncertain; however, it has been suggested that it may be related to a decrease in inflammation and tissue fibrosis. Collagen type III (COL III) is one of the major constituents of the extracellular matrix in different organs and is markedly upregulated in fibrotic conditions. In this study, we examined the effect of canagliflozin treatment on biomarkers of COL III turnover in the CANVAS trial.

Methods

Fragments reflecting COL III formation (PRO-C3) and degradation fragments of both cross-linked (CTX-III) or non-cross-linked COL III (C3M) were assessed with ELISA in plasma (n=2141, 1549, 2155, respectively). The change in biomarker levels from baseline to year 3 were investigated in plasma samples from both placebo (PBO)- and canagliflozin (CANA)-treated patients using a linear model. Investigated outcomes included all-cause mortality (n=116). Hazard ratios (HR) with 95% CI represent a comparison of the 75^th percentile versus 25^th percentile. The p-values presented are derived from a Wald test.

Results

At follow-up,PRO-C3 was significantly lower (p<0.0001; Figure 1A) and CTX-III was significantly higher in CANA-treated patients compared to PBO-treated patients (p=0.0002; Figure 1B). There was no impact on C3M (p=0.06, not shown).
In the entire cohort, an increase in PRO-C3 was significantly associated with all-cause mortality (HR [95% CI] = 1.07 [1.05-1.10], p<0.0001). The prognostic ability of an increase in PRO-C3 to predict all-cause mortalitywas significantly higher in the PBO-treated patients than in the CANA-treated patients (1.28 [1.11-1.47] vs 1.07 [1.04-1.10], p=0.04).

Conclusion

The observed decrease in fragments reflecting COL III formation, as well as the increase in cross-linked COL III degradation fragments following canagliflozin treatment may reflect the anticipated potential anti-fibrotic effect of the treatment. An increase in COL III formation was associated to an increase in the risk of all-cause mortality.

Funding

• Commercial Support – Janssen and Nordic Bioscience